Before there was a Lynchburg there was a ferry. In 1757, seventeen-year-old John Lynch began running boats across the James River at the confluence with Blackwater Creek, and the road that climbed up the south bank from the landing became the founding artery of the town. That road, originally called Seventh Alley, was later renumbered Fifth Street. From the late eighteenth century forward it ran from the ferry south toward New London, passing the lot John Lynch and his wife Mary donated for a public burying ground in 1806 — what would become Old City Cemetery. Two of Lynchburg's three surviving early-nineteenth-century taverns still stand on this corridor: the Kentucky Hotel at 900 Fifth Street, sections of which date to about 1800, and the Western Hotel (also called Nichols' Tavern) at 600 Fifth, built in 1815 after a fire destroyed its predecessor. Both are five-bay Flemish-bond brick buildings with the elegant fanlights and 6/9 sash that mark the Federal style.

Lynchburg made its nineteenth-century fortune on tobacco — leaf bought from Piedmont farmers, processed in city factories, twisted and pressed into plugs, and shipped down the James. Two of the largest tobacco factories from that era stand in the district at 409 and 410 Court Street, both built between 1877 and 1885. They are massive gable-fronted brick buildings, three stories of working space behind elaborate brickwork concentrated on the street-facing gable ends, where ornament could announce a firm's prosperity. Inside, much of the labor was done by African Americans, paid piecework wages, working the leaf into the product that paid for most of downtown's brick and most of Lynchburg's nineteenth-century wealth.

By the late nineteenth century, with segregation hardening into law, Fifth Street had become the commercial heart of Black Lynchburg — and it stayed that way for nearly a century. The Humbles Building of 1915, three stories of yellow brick at 901 Fifth Street, housed Black-owned offices and storefronts. The M.R. Scott Meat Market at 700 Fifth, designed in 1919 by local architects Craighill and Cardwell with the proprietor's name carved in Vermont white marble and panels of antique verde marble above the storefront, was one of the most architecturally refined buildings on the street. The Fifth Street Baptist Church of 1929, the Community Funeral Home of 1922, the Moser Furniture Company of 1936 — these were the everyday institutions where a community organized its life. The Tal-Fred Apartments, built in 1940, gave Black residents quality multifamily housing at a time when most landlords would not rent to them.

The early automobile age left its mark too. Miller Tire and Battery Company at 400 Fifth, built in 1927, originally had a diagonal porte-cochere that let drivers stop at the office without leaving their cars. The Adams Motor Company building at 811 Fifth, also 1927, was a triple-bay showroom for three different car retailers, its arched glazed fanlights lighting the floor. The Burnett Tire Company at 403 Fifth, designed in 1956 by Cress and Johnson, has the angular glass storefront of a future that no longer feels quite so futuristic. By the 1960s the district was hurting. Highway routing — Fifth Street had been part of U.S. 29 from 1931 to 2005 — emptied it of foot traffic. Urban renewal of the 1960s and 70s cleared blocks elsewhere in town. But Fifth Street largely survived. The honorary designation as Martin Luther King, Jr. Boulevard reflects what the corridor meant and means. The 2012 listing on the National Register made it official.